美国南加州大学Darryl Shibata、英国伦敦玛丽女王大学Trevor A. Graham和美国莫菲特癌症中心Alexander R. A. Anderson研究团队合作取得最新进展。他们在人体组织中以高时间分辨率进行细胞谱系追踪波动甲基化时钟 (FMC)。2022年1月3日出版的《自然—生物技术》杂志发表了这项成果。

他们表明波动的 DNA 甲基化标记可以用作细胞中的时钟，其中正在进行的甲基化和去甲基化导致甲基化和非甲基化状态之间重复“触发器”。他们使用标准甲基化阵列识别内源性波动 CpG (fCpG) 位点，并开发数学模型以从这些数据中定量测量成人干细胞动力学。推测小肠隐窝含有比结肠略多的干细胞，小肠中的干细胞置换速度较慢。

种系 APC 突变增加了每个隐窝的替换数量。他们测量了血液中急性白血病的快速扩张和慢性病的缓慢增长。 因此，人类体细胞生成和死亡的模式可以通过(FMC)进行测量。

研究人员表示，记录细胞祖先的分子钟突变太慢，无法测量成体组织中细胞更新的短时间尺度动态。

附：英文原文

Title: Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues

Author: Gabbutt, Calum, Schenck, Ryan O., Weisenberger, Daniel J., Kimberley, Christopher, Berner, Alison, Househam, Jacob, Lakatos, Eszter, Robertson-Tessi, Mark, Martin, Isabel, Patel, Roshani, Clark, Susan K., Latchford, Andrew, Barnes, Chris P., Leedham, Simon J., Anderson, Alexander R. A., Graham, Trevor A., Shibata, Darryl

Issue&Volume: 2022-01-03

Abstract: Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated ‘flip–flops’ between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).

DOI: 10.1038/s41587-021-01109-w

Source: https://www.nature.com/articles/s41587-021-01109-w